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Effects of overexpression of HKDC1 on gene expression in two colon cancer cells.

ABSTRACT: Dysregulation of cellular metabolism is one of the hallmarks of cancer. Tumor cells would enhance glycolysis to fuel the phenotypes of rapid proliferation and invasion. This study aims to explore epigenetic reprogramming of glycolysis pathway in colorectal cancer (CRC). CRCs and the adjacent normal colon tissues were profiled by using a comprehensive methylation array (Illumina Methylation EPIC Beadchips) to comprehensively analyze the methylation alterations in the glycolysis pathway. Differentially methylated genes (DMGs) were identified by using β value difference (≧ 0.2 or ≦ -0.2) and Wilcoxon rank-sum test (p < 0.05), and the common DMG in open datasets (GSE42752, GSE25062 and TCGA). Pyrosequencing was executed to validate the DMGs. Hexokinase domain containing 1 (HKDC1), the major hypomethylated gene we found, was overexpressed in colon cancer cells. Cells were treated with an HKDC1 inhibitor to elucidate the role of HKDC1. We found hypomethylation of HKDC1 was the only shared hypomethylated DMG in glycolysis pathway after comparing our methylation profiles of CRC to 3 public datasets. The RT-qPCR study in our cohort supported HDKC1 expression is methylation-regulated. Overexpression of HKDC1 in colon cancer cells resulted in increased proliferation of colon cancer cells and decreased cytotoxicity by an HKDC1 inhibitor. RNA sequencing revealed significant up-regulation of glycolysis and cell cycle pathways and their targets in HKDC1 overexpressed cells. In summary, hypomethylation of HKDC1 is common in CRC and may regulate cellular metabolism to promote proliferation of colon cancer cells through upregulation of glycolysis and cell cycle pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308712 | GEO | 2026/04/22

REPOSITORIES: GEO

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Project description:Background: An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African Americans (AAs) consume greater quantities of fructose and are more likely to develop right-side colon cancer than European Americans. Objective: We examined the hypothesis that fructose consumption leads to genomic differences associated with CRC tumor biology. Methods: DNA methylation data from this study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of fructose consumption in normal AA colon biopsies (n=79) undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Right colon organoids derived from AA normal colon tissues were exposed to 4.4mM of fructose for 72 hours. Fructose-associated differentially expressed genes (DEGs) were identified using DESeq2. This package was also used to identify DEGs in CRC tumors from TCGA-COAD. Results: We identified 4,263 right colon fructose-associated DMRs (FDR<0.05). In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in at least one of three datasets. A highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in AA right colon organoids (P=3.28E-30). Further, overlapping and significant enrichments for a number of fatty acid metabolism, glycolysis and cell proliferation pathways were also found. By further examining the overlap of genes within these pathways that were also differentially expressed in TCGA-COAD, our analysis reveals potential role for PFKP and ANKRD23 in fructose-mediated CRC risk. Conclusions: Our data support that dietary fructose exerts a greater CRC risk-related effect in right than left colon among AAs, alluding to its potential role in contributing to racial disparities in CRC.

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Effects of overexpression of HKDC1 on gene expression in two colon cancer cells.

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